3,6′-Dithiothalidomide (42 mg/kg i.p. once daily × 6 weeks) attenuated age-associated changes in hallmark features of AD in old 3xTg-AD animals. Two cohorts of 3xTg-AD mice, adult and old, were evaluated after a 6-week regimen with daily administration of 3,6′-dithiothalidomide or vehicle. After completion of the Morris Water Maze assessment animals were euthanized, and the levels of hallmark features of Alzheimer’s disease were assessed. (A) Treatment with drug (n = 9) significantly reduced the levels of total APP in the old animals vs. old control animals (n = 7). (B) Cortical soluble Aβ1–42 levels were increased in the old + control animals compared to younger adult + control (n = 7–9, P < 0.01). Drug treatment reduced the soluble Aβ1–42 in the old mice (n = 8), but not in younger adult ones. (C) Levels of total tau protein were lower in old control animals compared to younger adult control mice; however, drug treatment had no effect on total tau levels in either age group. (D) Phosphorylated tau protein levels were elevated in old animals compared to younger adult animals (n = 8–9). Treatment of the old animals with drug reduced levels of phosphorylated tau protein. The levels of SNAP 25 (E) and synaptophysin (F) were elevated in old drug-treated mice (P < 0.01 and P < 0.05, both n = 7–9, respectively), compared to old vehicle animals. Data are presented in percent change from appropriate control terms and are expressed as mean ± SEM of n observations; levels of statistical significance are indicated as follows: *P < 0.05, **P < 0.01, ***P < 0.001.